In a prospective study extending up to 19 years, beta cell function has been serially assessed in 25 monozygotic twins initially discordant for Type I diabetes mellitus. Currently, continuation of this prospective study is threatened because of lack of funding of a larger NIH grant of which this particular project was a small part. In this present proposal we request funds to enable us a) to continue prospective follow-up of these unique individuals to determine if they convert to immunologic abnormality or endocrine dysfunction, b) to study more twins with our new conceptual framework concerning the time course of the development of diabetes, c) to apply recently developed and ongoing immunologic techniques and correlate this with endocrine function and d) to probe the events surrounding conversion to immunological abnormality. On the basis of five of the prospectively studied monozygotic twins who developed Type I diabetes we have evidence that there is a progressive slow loss of first phase insulin release associated with immunologic abnormalities which precedes glycemic abnormalities. Our preliminary data now indicates that response to intravenous glucose is the most sensitive indicator of progressive beta cell dysfunction and we propose to concentrate on that parameter to enable us to truly define if the loss is as linear as it appears. Extended haplotype HLA typing, islet-cell antibodies (cytoplasmic and new surface), T cell activation antigens, insulin and glucagon release and at the time of immunologic conversion, multiple autoantibodies, viral titers, viral cultures and T cell analyses will be applied to better define the pathogenesis of Type I diabetes.